Alkoxylated benzoic acid esters of yohimbyl alcohol



2,785,164 Patented Mar. 12, 1957 ALKOXYLATED BENZOIC ACID ESTERS F YOHIMBYL ALCOHOL Walter Voegtli, Evanston, and Richard A. Robinson, Morton Grove, 11]., assignors, by mesne assignments,

to G. D. Searle & Co., Skokie, 111., a corporation of Delaware No Drawing. Application October 14, B 54,

Serial No. 462,384

. 6 Claims. (Cl. 260-287) This invention relates to certain esters of yohimbyl alcohol which have been found to have valuable pharmacological properties. More particularly, it relates to alkoxylated benzoic acid esters of yohimbyl alcohol which can be represented by the formula and salts thereof wherein one of the groups A and B is selected from the class consisting of methoxybenzoyl, dimethoxybenzoyl, and trimethoxybenzoyl, and the other is selected from the class consisting of methoxybenzoyl, dimethoxybenzoyl, trimethoxybenzoyl and hydrogen.

Yohimbyl alcohol has the formula and is structurally related to the naturally-occurring alkaloid yohimbine which has the formula vascular system. The responses usually produced by an increase in the secretion of epinephrine are those of vasoconstriction, stimulation of the heart muscle, increased blood pressure, and increased cardiac output. However, these important vasopressor effects of epinephrine are not elicited in the presence of yohimbine. Instead, following the administration of yohimbine, the effect of epinephrine is to produce a marked fall in blood pressure of relatively brief duration. This effect of epinephrine reversal is believed to result by the following mechanism: Under normal circumstances epinephrine can stimulate both constrictor and dilator adrenergic nerve fibers leading to the arterioles, but the net response is One of vasoconstriction. However, in the presence of a drug such as yohimbine which produces epinephrine reversal, the vasoconstrictor nerve fibers are paralyzed and only the dilator nerve fibers are stimulated, resulting in a fall in blood pressure. p

The normal cardioaccelerator and vasoconstrictor responses to epinephrine are important as a means of adjusting the blood pressure of an individual to the varying demands of his environment. For example, when these normal responses are lacking, the assumption of an erect posture is accompanied by a deleterious fall in blood pressure, resulting in a condition known as orthostatic or postural hypotension. Similarly, the initiation of exercise is not accompanied by the immediate rise in blood pressure required by the increased activity.

It is an object of this invention to produce, and to provide methods for producing, compounds which retain the hypotensive effect of yohimbine without destroying the normal pressor responses to epinephrine. Yohimbyl alcohol, a reduction product of yohimbine, exhibits potent hypotensive efiects but also suffers from the disadvantage of producing epinephrine reversal. However, it has now been found that when yohimbyl alcohol is esterified with anhydrides of aromatic acids substituted by one or more methoxyl groups, esters result which retain the hypotensive properties of yohimbine and of yohimbyl alcohol but which have their inhibitory etiect on epinephrine so markedly curtailed that in some instances they no longer produce the phenomenon of epinephrine reversal, and thus permit the treatment of hypertensive states without reversing the normal pressor responses to epinephrine.

The esters which constitute this invention are conveniently prepared by the reaction of yohimbyl alcohol with an aromatic acid anhydride, using a tertiary amine such as pyridine as a solvent.

The aromatic acid anhydrides which are employed in preparing the compounds of this invention are those derived from such acids as anisic acid (p-methoxybenzoic acid), veratric acid (3,4-dimethoxybenzoic acid) and 3,4,5-trimethoxybenzoic acid. When two molecular equivalents of the aromatic acid anhydride are used for each molecular equivalent of yohimbyl alcohol, a di-ester predominates in the reaction product. In these products both the primary and secondary hydroxyl groups of yohimbyl alcohol are esterified by the aromatic acid. \Vhenapproximately one molecular equivalent of the aromatic acid anhydride is used for each molecular equivalent of yohimbyl alcohol, a mono-ester predominates in the reaction product, and it is believed that these monoesters are those derivatives in which the primary alcoholic hydroxyl group has been esterified.

The bases described herein form salts, which are nontoxic in therapeutic dosage, with a variety of inorganic and strong organic acids such as phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, acetic, maleic, malic, succinic, tartaric, citric, ascorbic, gluconic, benzoic, cinnamic, or related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic, and aromatic sulfonic acids. Among such esters are methyl chloride, bromide, and iodide; the ethyl halides, propyl halides, butyl halides, isobutyl halides, benzyl halides, phenethyl halides, naphthylmethyl halides, im s l te, me sn n ul q at e yl luene s l p ts t y -.h. yd t y ene em hv rin the propylene halohydrins, allyl chloride, methallyl bromide, and crotyl bromide.

The quaternary ammonium salts of the bases described 'herein have a special utility as pharmacological agents, as they not only exhibit hypotensive properties without epinephrine reversal, but in addition actuallypotentiate the effect of epinephrine.

The methods of preparation and properties of these compounds will be more apparent from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope Example 1 Yohimbyl alcohol hemihydrate (3.1 parts) is converted to the anhydrous material by dissolving it in 85 parts of xylene and removing the solvent by distillation in a vacuum. Pyridine (45 parts) and trimethox'ybenzoic anhydride (7.6 parts) are added to the residue and the reaction mixture is heated for 24 hours under reflux in a nitrogen atmosphere. The residue remaining after removal of the solvent is dissolved'in 220 parts of chloroform and the chloroform solution is extracted with several portions of cold sodium bicarbonate solution and with several portions of water. All aqueous extracts are discarded. The residue obtained from the chloroform solution by distillation of the solvent is extracted with 180 parts of ether. The insoluble material is dissolved in 9 parts of benzene and 180 parts of ether is added. The precipitate which forms is collected'and discarded and the combined ethereal solution, which contains about 2 volume percent of benzene, is poured on an alumina chromatography column. 'Eluates are obtained from the column with additional portions of a 2 volume pera cent solution of benzene in ether. The material obtained by elution with this solvent mixtureis purified by recrystallization from methanol containing a small amount of petroleum ether. In this manner there is obtained the div(3,4,5-trimeth0xybenzoic acid ester) of yohimbyl alcohol as a white crystalline product. When the melting point is taken at atmospheric pressure, excessive decomposition tends to make the determination unsatisfactory. In a high vacuum the compound melts fairly sharply and under these conditions evidence has been obtained that the compound can exist in two polymorphic forms melting at 143-l44 C. and at l62.-16 3 C. The melting point of the lower melting form isnot depressed by adil s t e higher mel n s mis pound has the structural formula a nue Example 2 Yohimbyl alcohol hernihydrate (3.1 parts) is converted to anhydrous material by dissolving it in 85 parts of xylene and distilling off the isolvent in a vacuum. To the residue there are added parts of pyridine. and .7 parts or" veratric'anhydride. This reaction mixture is heated under reflux in a nitrogen atmosphere fo'r a period of 22 hours," at the end of'which time the solvent is, removed by vacuum distillation. Theresidueisthen dissolved in 2 20 parts of'chloroform and this solution is freed of verat-ric acid byrepeated extraction with cold sodium bicarbonate solution. The bicarbonate extractions are continued until an extract is obtained which no longer yields a precipitate when acidified with .dilute hydrochloric acid. The chloroform'phase is then washed with 3 portions of ice water, and all aqueous extracts are discarded. The nonrvolatile residue obtained from the organic phase after removal of the chloroform by distillation is, extracted with, 180 parts'of ether. The residue which remains undissolved by this treatment is dissolved in '9' parts of benzene. Ether (180 parts) is added to the benzene solution and the precipitate which forms is collected and discarded.

The combined ethereal solution containing about 98 7 volume percent ether aud 2 volume percent benzene is poured on a chromatography column containing parts of alumina, and the column is eluted with further portions of a solution of benzene in ether containing about 2 V The fractions eluted from the column in this manner are evaporated to dryness in a 7 volume percent of benzene.

. This compound has the structural formula OCHs When a solution of this free base in a mixture of henzene and ether containing about 10 volume percent of benzene is treated with a slight excess of ethanolic hydrogen chloride, the hydrochloride precipitates as an insoluble oil.

Example 3 Yohimbyl alcohol hemihydrate 3.1 parts) is converted to anhydrous material by dissolving it in 85 parts of xylene and distilling off the solvent in a vacuum. To

tion until the basic extracts no longer yield a precipitate V of p-methoxybenzoiclacid when acidified. with dilute hyo hlor id. Th hloroformiphase is thenwashed with hree port ns. of i e water: and. a aque us extrac .1 {var are discarded. The non-volatile residue obtained from the organic phase after removal of the chloroform is extracted with 180 parts of ether. The residue which remains undissolved by this treatment is dissolved in 9 parts of benzene. Ether (180 parts) is added to the benzene solution and the precipitate which forms is collected and discarded. The combined ethereal solution containing about 98 volume percent ether and 2 volume percent benzene is poured on a chromatography column made up with 50 parts of alumina and the column is I eluted with further portions of a solution of benzene in ether containing about 2 volume percent of benzene. The eluates obtained from the column are evaporated to dryness in a nitrogen atmosphere. When a solution of the residues in a small amount of benzene is diluted with petroleum ether, the di-(p-methoxybenzoic acid ester) of yohimbyl alcohol precipitates. It is obtained as a purified amorphous powder by dissolving it in a mixture of benzene and ether and reprecipitating by the addition of petroleum ether. This compound has the structural formula Iii-Z Example 4 Yohimbyl alcohol hemihydrate (3.1 parts) is converted to the anhydrous material by dissolving it in 85 parts of xylene and removing the solvent by distillation in a vac uum. Pyridine (45 parts) and trimethoxybenzoic anhydride (3.8 parts) are added to the residue and the mixture is heated under reflux in a nitrogen atmosphere for 24 hours. The solvent is then removed from the mixture by a vacuum distillation and the residue is dissolved in 220 parts of chloroform. The chloroform solution is washed repeatedly with cold sodium bicarbonate solution and then with several portions of ice water. All aqueous extracts are discarded and the organic phase is evaporated to dryness. The non-volatile residue which remains after removal of the chloroform is extracted with 180 parts of ether. The residue which remains undissolved by this treatment is dissolved in 9 parts of benzene. Ether (180 parts) is added to the benzene solution and the precipitate which forms is collected and discarded. The combined ethereal solution containing about 98 volume percent ether and 2 volume percent benzene is poured on a chromatography column containing 40 parts of alumina and the column is eluted with further portions of a solution of benzene in ether containing about 2 volume percent of benzene. The fractions eluted from the column in this manner are evaporated to dryness in a nitrogen atmosphere. When a solution of the residues in a small amount of benzene is diluted with petroleum ether, the mono-(3,4,5-trimethoxybenzoic acid ester) of yohimbyl alcohol is precipitated. For purification this material is dissolved in a mixture of benzene and ether containing about 12 volume percent of benzene and filtered from a small amount of insoluble material, which is discarded. When the filtrate is diluted with petroleum ether, the purified amorphous ester precipitates and is collected on a filter and washed with petroleum ether. In a high vacuum this compound melts from about 125-135 C. It is believed to have the following structural formula O a? omo-Q- -o-om- 0 onto 11 When a solution of this free base in a mixture of benzene and ether containing about 10 volume percent of benzene is treated with a slight excess of ethanolic hydrogen bromide, the hydrobromide precipitates as an insoluble oil.

Example 5 CHAS Example 6 A mixture of 3.0 parts of yohimbyl alcohol (prepared from 3.1 parts of the hemihydrate by drying with xylene in the usual manner), 45 parts of pyridine and 2.8 parts of p-methoxybenzoic anhydride is heated under reflux in a nitrogen atmosphere for a period of 24 hours. The reaction mixture is Worked up and the product is isolated and purified exactly in the manner of Example 4. There is thus obtained the mono-(p-methoxybenzoic acid ester) of yohimbyl alcohol as an amorphous material. This compound probably has the structural formula Example 7 Yohimbyl alcohol hemihydrate (2.05 parts) is converted to the anhydrous material by dissolving it in parts of xylene and removing the solvent by distillation in a vacuum. A mixture of the residue, 30 parts of pyri- 'an alumina chromatography column.

dine and 3.20 parts of benzoic anhydride is heated under reflux for 24 hours in a nitrogen atmosphere and then allowed to stand for an additional 2 days at room temperature. The pyridine is removed by distillation in a. vacuum and the non-volatile residue is dissolved in a mixture of benzene and ethyl acetate. The organic solution is extracted repeatedly with portions of cold sodium bicarbonate solution in order to remove the benzoic acid. The organic phase is then Washed with several portions'of water and all aqueous extracts are discarded. The residue obtained when the organic solvents are removed by distillation in a vacuum is dissolved in mixture of ether and benzene containing'50 volume percent of each solvent component'and this solution is poured on When the chromatography column'is eluted with further portions of this solvent mixture, there is obtained the di-(benzoic acid ester) of yohimbyl alcohol. .For purification this compound is recrystallized from methanol. In this manner there is obtained a crystallizate, presumably a solvate, melting with decomposition at about 125 C.

Example 8 V Yohimbyl alcohol rhemihydrate (2.05 parts) is converted to the anhydrous material by dissolving it in 85 parts of xylene and removing the solvent by distillation in a vacuum. The residue dissolved int 3O parts of pyridine is treated by the addition of 1.52 parts of purified benzoic anhydride and the reaction mixture is heated under reflux in a nitrogen atmosphere for 24 hours. The solvent is then removed by distillation in a'vacuum and a solution of the residue in 370 parts of chloroform is extracted repeatedly with cold sodium bicarbonate solution and with water. i All aqueous extracts are discarded. The residue obtained by removal of the solvent from the organic phase is extracted with 140 parts of ether. This solution is filtered and the filtrate is poured on an alumina chromatography column. The column is eluted with further quantities-of ether and the residue obtained from these eluates is recrystallized from a mixture of ether and petroleum ether. In this manner there is obtained a purified mono-(benzoic acid ester) of yohimbyl alcohol which is believed to have the following structural formula chloride, a hydrochloride salt crystallizes, melting point about 292-293 C. t

V 7 Example :9 V Yohimbyl alcohol hemihydrate (1 part) is dissolved by warming with 5 partsof 98100% formic acid. This solution is allowed to stand at room temperature for 3 to' 4 days. It isthendiluted with water, chilled and treated 7 with a small excess of sodium bicarbonate solution. The free base which precipitates is collected on a filter and washed with Water. y recrystallization from methanol 5 washed with petroleum ether.

.material in 40 parts of ethyl alcohol and 85 parts of ether is treated by the addition of 3.7 parts of sulfuric there is obtained :the purified di-(formic acid ester) of yohimbyl alcohol. Determinations of the melting point of this compound are complicated by the decomposition.

which precedes and accompanies its fusion. When the temperature is raised very slowly, the compound begins to soften at about 118? C. and becomes liquid with gross decomposition, at about l28-.130 C.

Example 10 A r v aicoho; hem of acetic anhydride is allowed to stand at room tempe ature for 24 hours. The solvents are removed by a vacuum distillation and the residual oily product, which so siste principally of the salt formed by acetic acid mixture prepared from parts of yohimbyl allized from a mixture of'benzene and petroleum ether.

slight excess of saturated sodium bicarbonate solution and the crystalline free base which forms is extracted with ether. The ethereal solution is washed with water and then dried over anhydrous calcium sulfate and eva orated to dryness. When the residue which remains is recrystallized from aqueous methanol or from a mixture of benzene and petroleum ether, there is obtained the purified (ii-(acetic acid ester) of yohimbyl alcohol which melts with decomposition at 2S5205 C. When a solution of this free base in ethanol is treated with a slight excess of'ethanolic hydrogen chloride, the hydrochloride salt of the di-(acetic acid ester) crystallizes from the so lution. The yi ld of this product is improved by diluting the acidified mixture with ether. When the hydrochloride is purified by recrystallization from methanol or from mixtures of methanol and ether, there are obtained white crystals of this compound which do not melt at 320 C.

A solution of 1 partof the free base dissolved in 8 parts of methyl. ethyl ketone is treated by the addition of 5 parts of methyl bromide. This mixture is allowed to stand for 2 hours and then diluted with ether.. The

ture of methanol and petroleum ether yields the purified methio'dide of the di-(acetic acid ester) ofyohimbyl alcohol, melting with decomposition at '286287 C.

Example 11 A solution of ,2 parts of yohimbyl alcohol hernihydrate, parts of pyridine and 10 parts of propionic anhydride is allowed tostand for 2 days at room ternperature. The solvents are removed by a vacuum distillation. When the residue, diluted with ether, is treated by the addition of petroleum ether, the di-(propionic acid ester) of yohimbyl alcohol crystallizes from the mixture as the free base. 7 This product is collected on a filter and A filtered solution of this acid in 10 parts of ethyl alcohol and the resulting mixture is diluted with an additional '70 parts of etherv Crystals of thesulfuric acid salt of the diurcionic acid ester) of yohimbyl alcohol which separate are collected on a filter and Washed with ether. When this product is purified by recrystallization from ethyl alcohol (with .nydrate, 150 parts'of pyridine and parts the iii-(acetic acid-ester) of yohimbyl alcohol, is crys-' a. chilled aqueous solution of this material is treated with which it shows some tendency to form a solvate) it melts 3. A compound having the structural formula with decomposition at 281 C.

What is claimed is:

1. A compound having the structural formula 30) 0 A-O-CH 0H wherein n is a positive integer from 1 to 3 inclusive. 4. The di-(p-methoxybenzoic acid ester) of yohimbyl 4 wherein A is selected from the class cons1st1ng of methalcohoL ?YL dlmethcxybenzoyl and lfnmethoxybenzoyli 5. The di-(3,4-dimethoxybenzoic acid ester) of yohimand B is selected from the class consisting of methoxybyl alcohoL benzoy}, dimethoxybenzoyl tfimethoxybenzoyl and 113/ 6. The di-(3,4,5-trimethoxybenzoic acid ester) of yodmgenhimb 1 al ohol.

2. A compound having the structural formula y C References Cited in the file of this patent Dortmann et al.: Helv. Chim. Acta, vol. 37, pp. 59-

(0CH3)1\ wherein n is a positive integer from 1 to 3 inclusive. 

1. A COMPOUND HAVING THE STRUCTURAL FORMULA 